ZA200500484B

ZA200500484B - Thiazole derivatives as phosphodiesterase IV inhibitors

Info

Publication number: ZA200500484B
Application number: ZA200500484A
Authority: ZA
Inventors: Hans-Michael Eggenweiler; Michael Wolf
Original assignee: Merck Patent Gmbh
Priority date: 2002-06-19
Filing date: 2005-01-18
Publication date: 2006-04-26
Also published as: JP4555076B2; US7790723B2; JP2005530825A; PL372123A1; DE50304867D1; MXPA04012428A; US20050222160A1; EP1513837B1; AU2003232215B2; WO2004000839A1; RU2005101202A; BR0311879A; AU2003232215A1; EP1513837A1; AR039695A1; CA2489902A1; CA2489902C; ATE338041T1; ES2271642T3; DE10227269A1

Description

® WO 2004/000839 PCT/EP2003/004434 ®

THIAZOLE DERIVATIVES AS PHOSPHODIESTERASE IV INHIBITORS

The invention relates to compounds of the formula

R1

Daa NYO

R2 N—N WO

Ia

R3 in which

R'and R®> are each, independently of one another, H, OH, OR? -SR®, -SOR®, -SO,R® or Hal,

R'and R® together are alternatively -OCH,0- or -OCH,CH,0-,

R®and R® are each, independently of one another, H, A"R’, COA"R’,

COOA"R’, CONH,, CONHA"R’, CON(A"R)(A"R"),

CONR"Het, NH,, NHA"R’, N(A"R")(A"R"), NCOA"R’ or

NCOOA"R’,

Vand W are oxygen or hydrogen substituents, with the proviso that, if

Vis O, Wis HH, and vice versa,

B is an aromatic isocyclic or heterocyclic radical, which may be unsubstituted or monosubstituted, disubstituted or trisub- stituted by R*, R® and/or R®,

X is N or CR?,

R* R® and R® are each, independently of one another, H, A"R’, OH,

OA"R’. NO,, NH», NHA"R, N(A"R")(A""R"), NHCOA"R’,

NHCOOA"R’, NHCONH,, NHCONHA"R’,

NHCON(A"R”)(A"R’), Hal, COOH, COOA"R’, CONH;,

CONHA"R’, CON(A"R")(A"R’),

® 2

N N

ON { — xd

Y N= N= 0 \N 0

N H,N

Hp or =

NZ

R’ is H, COOH, COOA, CONH,, CONHA, CONAA', NH,, NHA,

NAA’, NCOA, NCOOA, OH or OA,

R® is A, cycloalkyl having 3-7 carbon atoms, alkylenecycloalky! having 4-8 carbon atoms or alkenyl having 2-8 carbon atoms,

R® is alkyl having 1-10 carbon atoms, cycloalkyl having 3-7 carbon atoms, alkylenecycloalkyl having 4-8 carbon atoms or alkenyl having 2-8 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO,, NH, NMe, NEt and/or by -CH=CH- groups, : and/or 1-7 H atoms may be replaced by F and/or Cl,

Y is alkylene having 1-10 carbon atoms or alkenylene having 2-8 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO,, NH or NR® and/or 1-7 H atoms may be replaced by F and/or CI,

Aand A’ are each, independently of one another, alkyl having 1-10 carbon atoms or alkenyl having 2-8 carbon atoms,

® WO 2004/000839 PCT/EP2003/004434 ® 3 in which one, two or three CH, groups may be replaced by 0, S, SO, SO,, NH or NR® and/or 1-7 H atoms may be replaced by F and/or Cl, or aryl or Het,

A and A together are alternatively an alkylene chain having 2-7 carbon atoms, in which one, two or three CH, groups may be replaced by O, S, SO, SO,, NH, NR’, NCOR® or NCOOR?®,

A" and A" are each, independently of one another, absent, alkylene having 1-10 carbon atoms, alkenylene having 2-8 carbon atoms or cycloalkylene having 3-7 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO,, NH or NR® and/or 1-7 H atoms may be replaced by F and/or Cl,

A" and A" together are alternatively an alkylene chain having 2-7 carbon atoms, in which one, two or three CH, groups may be replaced by O, S, SO, SO, NH, NR’, NCOR® or NCOOR?, aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubsti- tuted by Hal, R"', OR, N(R'),, NO,, CN, COOR",

CON(R'),, NR'°COR', NR'°CON(R'),, NR'°S0,A, COR",

SO.N(R"); or S(O).R",

R' is H or alkyl having 1-6 carbon atoms,

R" is alkyl having 1-6 carbon atoms,

Het Is a monocyclic or bicyclic saturated, unsaturated or aro- matic heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubsti- tuted by carbonyl oxygen, Hal, R'", OR, N(R'®),, NO,, CN,

COOR', CON(R"),, NR'°COR', NR'°CON(R'),,

NR'®SO,R"!, COR", SO,NR' and/or S(O)mR"",

Hal isF, Cl, Bror |,

® WO 2004/000839 PCT/EP2003/004434 ® 4 m is0, 1o0r2, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 1-Benzoyltetrahydropyridazines as progesterone receptor ligands are described, for example, in J. Med. Chem. 38, 4878 (1995).

Further arylalkanoylpyridazines are disclosed, for example, in

EP 0922 036, EP 1 124 809 or WO 01/04099.

The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

It has been found that the compounds of the formula | and salts and sol- vates thereof have very valuable pharmacological properties and are well tolerated.

The compounds of the formula | exhibit selective phosphodiesterase 1V inhibition which is associated with an intracellular increase of cAMP (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)). The PDE IV inhi- bition can be detected, for example, analogously to C.W. Davis in

Biochim. Biophys. Acta 797, 354-362 (1984).

The affinity of the compounds according to the invention for phospho- diesterase IV is determined by measuring their ICs, values (concentration of the inhibitor that is required in order to achieve 50% inhibition of the enzyme activity).

The compounds according to the invention can be employed for the treatment of asthmatic diseases. The anti-asthmatic action of the PDE IV inhibitors is described, for example, by T.J. Torphy et al. in Thorax, 46, 512-523 (1991), and can be determined, for example, by the method of

T. Olsson, Acta allergologica 26, 438-447 (1971).

® WO 2004/000839 PCT/EP2003/004434 ® 5

Since cAMP inhibits osteoclastic cells and stimulates osteogenetic cells (S. Kasugai et al., M 681, and K. Miyamoto, M 682, in Abstracts of the

American Society for Bone and Mineral Research, 18" Annual Meeting,

S 1996), the compounds according to the invention can be employed for the treatment of osteoporosis.

In addition, the compounds exhibit an antagonistic action to the produc- tion of TNF (tumour necrosis factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's dis- ease, diabetes mellitus or ulcerative colitis, transplant rejection reactions, cachexia and sepsis.

The anti-inflammatory action of the substances according to the invention and their effectiveness for the treatment of, for example, autoimmune dis- orders, such as multiple sclerosis or rheumatoid arthritis, can be deter- mined analogously to the methods of N. Sommer et al., Nature Medicine 1, 244-248 (19995), or L. Sekut et al., Clin. Exp. Immunol. 100, 126-132 (1995).

The compounds can be employed for the treatment of cachexia. The anti- cachectic action can be tested in TNF-dependent models of cachexia (P. Costelli et al., J. Clin. Invest. 95, 2367ff. (1995); J.M. Argiles et al,

Med. Res. Rev. 17, 477 ff. (1997)).

PDE IV inhibitors can also inhibit the growth of tumour cells and are therefore suitable for tumour therapy (D. Marko et al., Cell Biochem. Bio- phys. 28, 75 ff. (1998)). The action of PDE IV inhibitors in the treatment of tumours is described, for example, in WO 95 35 281, WO 95 17 399 or

WO 96 00 215

® WO 2004/000839 PCT/EP2003/00:4434 ® )

PDE IV inhibitors can prevent mortality in models of sepsis and are there- fore suitable for the therapy of sepsis (W. Fischer et al., Biochem.

Pharmacol. 45, 2399ff. (1993)).

They can furthermore be employed for the treatment of memory disorders, atherosclerosis, atopic dermatitis and AIDS.

The action of PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, cachexia, tumour growth or tumour metastases is described, for example, in

EP 77 92 91.

The compounds of the formula | can be employed as medicament active ingredients in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active ingredients .

Furthermore, the invention relates to the use of type 4 phosphodiesterase inhibitors (PDE IV inhibitors) of the formula | for the treatment of diseases and relates to combinations of compounds of the formula | with other medicaments.

Reference is made to WO 01/57025 which discloses special pyrimidine derivatives as PDE IV inhibitors, the use thereof for the treatment of dis- eases and combinations with other medicaments.

Accordingly, the invention relates in particular to the use of compounds of the formula | and physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment of a patient suffering from a disease or condition mediated by the PDE IV isozyme in its role of regulating the activation and degranulation of human eosinophils.

® WO 2004/000839 PCT/EP2003/004434 ® 7 ments, which are capable of providing data sufficient to define and demonstrate therapeutic utility of compounds of the formula 1.

Compounds of the formula | inhibit the PDE IV isozyme and are therefore suitable for a wide range of therapeutic applications, because of the essential role which the PDE IV family of isozymes plays in the physiology of all mammals. The enzymatic role performed by the PDE IV isozymes is the intracellular hydrolysis of adenosine 3',5'-monophosphate (CAMP) within pro-inflammatory leukocytes. CAMP, in turn, is responsible for mediating the effects of numerous hormones in the body, and as a conse- quence, PDE IV inhibition plays a significant role in a variety of physio- logical processes. There is extensive literature in the art describing the effects of PDE inhibitors on various inflammatory cell responses, which in addition to cAMP elevation, also include inhibition of superoxide produc- tion, degranulation, chemotaxis and tumour necrosis factor (TNF) release in eosinophils, neutrophils and monocytes.

The invention therefore relates to the compounds of the formula | and to a process for the preparation of compounds of the formula | and salts and solvates thereof, characterised in that a) for the preparation of a compound of the formula | in which V is HH and Wis O, a compound of the formula ll

R?

R2 N—N in which

R' and R? are as defined in Claim 1, is reacted with a compound of the formula lll

® WO 2004/000839 PCT/EP2003/004434 ® 8 ©

I 1]

R3 in which

L is Cl, Br, lor a free or reactively functionally modified OH group, and R® X and B are as defined in Claim 1, with the proviso that any further OH and/or amino group present is pro- tected, and subsequently, if desired, a protecting group is removed, and/or b) one or more radicals R' R? R’>and/orBin a compound of the formula | are converted into one or more other radicals R', R?, R® and/or B by i) cleaving an ether or ester, ii) alkylating or acylating an OH function, iii) reductively alkylating an amino group, iv) reacting an amino group with malononitrile, v) converting a cyano group into a tetrazole group, and/or in that a basic compound of the formula | is converted into one of its salts by treatment with an acid.

In addition, the invention relates to the optically active forms (stereo- isomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. The term solvates of the compounds is taken to mean adductions of inert solvent molecules onto

® WO 2004/000839 PCT/EP2003/004434 ® 9 the compounds which form owing to their mutual attractive force. Solvates are, for example, monohydrates, dihydrates or alcoholates.

The term pharmaceutically usable derivatives is taken to mean, for exam- ple, the salts of the compounds according to the invention and so-called prodrug compounds.

The term prodrug derivatives is taken to mean, for example, compounds of the formula | which have been modified, for example, with alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism and thus release the active ingredients according to the inven- tion.

These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

The following abbreviations are used below:

Ac acetyl

BOC tert-butoxycarbonyl

CBZorZz benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DCM dichloromethane

DMF dimethylformamide

EA ethyl acetate

EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbodiimide

Et ethyl

Fmoc 9-fluorenylmethoxycarbonyl

HOBt 1-hydroxybenzotriazole

Me methyl

MBHA 4-methylbenzhydrylamine

Mtr 4-methoxy-2,3,6-trimethylphenyisulfony!

HONSu N-hydroxysuccinimide

® WO 2004/000839 PCT/EP2003/004434 ® 10

OBut tert-butyl ester

Oct octanoy!

OMe methyl! ester

OEt ethyl ester

S POA phenoxyacetyl

TFA trifluoroacetic acid

Trt trityl (triphenylmethyl).

The meanings of all radicals which occur more than once are in each case independent of one another.

Above and below, the radicals R', R?, R®> V, W, X, B and L are as defined in the formulae |, If and Ili, unless expressly stated otherwise.

Alkyl having 1-10 carbon atoms is alkyl having 1, 2, 3,4, 5,6, 7, 8,9 or 10 carbon atoms, is branched or unbranched, and is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and is, for example, methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermore preferably iso- propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decy!.

Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, further- more also cycloheptyl; particular preference is given to cyclopentyl.

Alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobutenyl or sec-butenyl: preference is furthermore given to 4-pentenyl, isopentenyl or 5-hexenyl.

Alkylene is preferably unbranched and is preferably methylene or ethyl- ene, furthermore preferably propylene or butylene.

® WO 2004/000839 PCT/EP2003/004434 ® 11

Alkylenecycloalky! is, for example, cyclohexylmethyl or cyclopentylethyl.

Alkyl having 1-6 carbon atoms is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, is branched or unbranched, and is, for example, methyl, ethyl, 5) trifluoromethyl, pentafluoroethyl or propyl, furthermore preferably iso- propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl or n-hexyl.

Hal is preferably F, Cl or Br, furthermore also |.

The radicals R' and R®> may be identical or different and are preferably in the 3- or 4-position of the phenyl ring. They are, for example, independ- ently of one another, H, hydroxyl, -S-CHj;, -SO-CHs;, -SO,CHj5, F, CI, Bror | or together are methylenedioxy. However, they are preferably each methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, or alternatively fluoro-, difluoro- or trifluoromethoxy or 1-fluoro-, 2-fluoro-, 1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy. in a further embodiment, R' and R? are each, independently of one another, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms.

Alkoxy has 1, 2, 3, 4, 5 or 6 carbon atoms and is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, cyclopentyloxy or cyclohexyloxy.

In a further embodiment, R' and R? are each, independently of one another, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms.

Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy or hexoxy.

® WO 2004/000839 PCT/EP2003/004434 ® 12

R'is particularly preferably ethoxy, benzyloxy, F, propoxy or isopropoxy, furthermore difluoromethoxy or cycloalkoxy, for example cyclopentoxy.

R'is very particularly preferably 4-methoxy or 4-ethoxy.

R? is particularly preferably methoxy, ethoxy, propoxy, F or ethyl, further- more difluoromethoxy or cycloalkoxy, for example cyclopentoxy.

R? is very particularly preferably 3-methoxy, 3-ethoxy, 3-propoxy, 3- isopropoxy or 3-cyclopentyloxy.

R® is preferably H, A"R’, COA"R’, CON(A"R")(A"R’) or CO-NR'"-Het, particularly prefeably H or A"R’.

In a further embodiment, R® is preferably, for example, H, COOH,

CO-CH;-NAA', CO-CH,-CH»-NAA', CO-CH,-NHA' or CO-CH>-CH>-NHA'.

R® is particularly preferably H.

X is preferably N or CH, very particularly preferably N.

B is an aromatic isocyclic radical, such as, for example, phenyl, naphthyl, fluoreny! or biphenyl, or a heterocyclic radical, where the radicals are unsubstituted or may be monosubstituted, disubstituted or trisubstituted by R?*, R® and/or R®, and where the heterocyclic radical is preferably a monocyclic saturated or unsaturated heterocycle having 1to 2 N, O and/or S atoms.

B is preferably phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyi, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thia- zolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl, isoquinotinyl, cinno- linyl, phthalazinyl, quinazolinyl or quinoxalinyl, each of which is unsub- stituted or may be monosubstituted, disubstituted or trisubstituted by R*

R® and/or R®.

® WO 2004/000839 PCT/EP2003/004434 ® 13

In a further preferred embodiment, B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxa- zolinyl, oxazoliny!, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl, quino- linyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazoliny! or quinoxalinyl, each of which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted by OH, OA, NO,, NH,, NAA"

N N

/\ _H / H / yoo he

N H,N

N

A I/ \ or N=

N

7

N_ _N

N 7

In a further preferred embodiment, B is unsubstituted pyridyl, pyridyl N- oxide, thienyl or pyrazinyl.

R* R® and R® are preferabiy H.

R’ is preferably H, COOH, NHA or NAA, very particularly preferably H.

R® is preferably R'", cycloalkyl having 3-7 carbon atoms or alkylene- cycloalkyl having 4-8 carbon atoms.

R® is preferably alkyl having 1-10 carbon atoms, very particularly prefera- bly alkyl having 1-6 carbon atoms.

Y is preferably methylene, ethylene, propylene or butylene.

® WO 2004/000839 PCT/EP2003/004434

A and A' are preferably each, independently of one another, alkyl having 1-10 carbon atoms, in which 1-7 H atoms may be replaced by F and/or Cl, or are each, independently of one another, aryl or Het.

A" and A" are preferably each, independently of one another: absent or alkylene having 1-10 carbon atoms, in which one CH; group may be replaced by NH or NR®.

A" and A" are preferably together alternatively an alkylene chain having 2-7 carbon atoms, in which one CH, group may be replaced by NH or

NR®.

Aryl is, for example, unsubstituted phenyl, naphthyl, fluorenyl or biphenyl, furthermore preferably phenyl, naphthyl, fluorenyl or biphenyl, each of which is monosubstituted, disubstituted or trisubstituted, for example, by methyl, ethyl, propyl, butyl, fluorine, chlorine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propio- nyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, sulfonamido, methylsulfonamido, ethylsulfonamido, propyl- sulfonamido, butylsulfonamido, dimethylsulfonamido, carboxyl, methoxy- carbonyl, ethoxycarbonyl or aminocarbony!|.

Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol- 1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-o0xa- diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-y|, 1,2 4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz- i

® WO 2004/000839 PCT/EP2003/004434 ® 15 2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benz-1,4- oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6- yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or completely hydrogen- ated.

Het can thus also be, for example, 2,3-dihydro-2-, -3-, 4- or -5-furyl, 2,5- dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5- dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro- 1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetra- hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benz-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxy- phenyl, 2, 3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoro- methylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3-(2- oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7- yl, furthermore preferably 2,3-dihydrobenzofurany! or 2,3-dihydro-2-oxo- furanyl.

In a further embodiment, Het is particularly preferably unsubstituted pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imida- zolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quina- zolinyl or quinoxalinyl, very particularly preferably pyridyl.

Claims

® WO 2004/000839 PCT/EP2003/004434 ® 96 Patent Claims

1. Compounds of the formula R! Eh R2 N—N S "as o Ro in which R'and R® are each, independently of one another, H, OH, OR®, -SR®, -SOR® -SO,R® or Hal, R'and R? together are alternatively -QCH,0- or -OCH,CH,O-, R®and R® are each, independently of one another, H, A"R’, COA"R’, COOA"R’, CONH,, CONHA"R’, CON(A"R"}(A"R"), CONR'’Het, NH,, NHA"R?, N(A"R’)(A"R’), NCOA"R’ or NCOOA'R’, Vand W are oxygen or hydrogen substituents, with the proviso that, if Vis O, Wis HH, and vice versa, B is an aromatic isocyclic or heterocyclic radical, which may be unsubstituted or monosubstituted, disubstituted or trisub- stituted by R*, R® and/or R® X is N or CR?, RY R® and R® are each, independently of one another, H, A"R’, OH, OA"R’. NO,, NH,, NHA"R”, N(A"R’)(A"R"), NHCOA"R’, NHCOOA'R’, NHCONH,, NHCONHA"R’, NHCON(A"R”)(A"R’), Hal, COOH, COOA"R’, CONH,, CONHA"R’, CON(A"R’}(A"R),

® WO 2004/000839 PCT/EP2003/004434 ® 97 N N hid N= N= 0 N 0 N HN Hg or =, i NZ R’ is H, COOH, COOA, CONH,, CONHA, CONAA', NH, NHA, NAA’, NCOA, NCOOA, OH or OA, 5S R® is A, cycloalkyl having 3-7 carbon atoms, alkylenecycloalkyl having 4-8 carbon atoms or alkenyl having 2-8 carbon atoms, R® is alkyl having 1-10 carbon atoms, cycloalkyl having 3-7 carbon atoms, alkylenecycloalkyl having 4-8 carbon atoms or alkenyl having 2-8 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO, NH, NMe, NEt and/or by -CH=CH- groups, and/or 1-7 H atoms may be replaced by F and/or Cl, Y is alkylene having 1-10 carbon atoms or alkenylene having 2-8 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO, NH or NR® and/or 1-7 H atoms may be replaced by F and/or Cl, Aand A are each, independently of one another, alkyl having 1-10 carbon atoms or alkenyl having 2-8 carbon atoms,

® WO 2004/000839 PCT/EP2003/004434 ® 98 in which one, two or three CH, groups may be replaced by 0, S, SO, SO, NH or NR® and/or 1-7 H atoms may be replaced by F and/or Cl, or S aryl or Het, A and A together are alternatively an alkylene chain having 2-7 carbon atoms, in which one, two or three CH, groups may be replaced by O, S, SO, SO, NH, NR®, NCOR® or NCOOR®, A" and A" are each, independently of one another, absent, alkylene having 1-10 carbon atoms, alkenylene having 2-8 carbon atoms or cycloalkylene having 3-7 carbon atoms, in which one, two or three CH, groups may be replaced by 0, S, SO, SO, NH or NR? and/or 1-7 H atoms may be replaced by F and/or Cl, A" and A" together are alternatively an alkylene chain having 2-7 carbon atoms, in which one, two or three CH, groups may be replaced by O, S, SO, SO, NH, NR®, NCOR® or NCOOR?, aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubsti- tuted by Hal, R'", OR", N(R"), NO», CN, COOR", CON(R™),, NR'COR', NR'CON(R™),, NR'*SO.A, COR",

SO.N(R™); or S(O)xR"", R' is H or alkyl having 1-6 carbon atoms, R" is alkyl having 1-6 carbon atoms, Het is a monocyclic or bicyclic saturated, unsaturated or aro- matic heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubsti- tuted by carbonyl oxygen, Hal, R"", OR’, N(R), NO, CN, COOR', CON(R'®),, NR'*COR'™, NR'’CON(R™);, NR'°SO,R'", COR'®, SO,NR'® and/or S(O).R", Hal isF, Cl, Bror |, oo Co [8

® 99 m is 0, 1or2, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

2. Compounds according to Claim 1, in which R'and R? are each, independently of one another, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compounds according to Claim 1, in which R'and R? are each, independently of one another, H, methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, difluoromethoxy, F, Ci, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compounds according to Claim 1, in which R'and R® are each, independently of one another, methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy or F, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

5. Compounds according to one or more of Claims 1-4, in which R' 4-methoxy or 4-ethoxy, R? is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or 3- cyclopentyloxy, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to one or more of Claims 1-5,

® WO 2004/000839 PCT/EP2003/004434 ® 100 in which R® is Hor A"R’, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

7. Compounds according to one or more of Claims 1-6, in which X is N or CH, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

8. Compounds according to one or more of Claims 1-7, in which B is an aromatic isocyclic or monocyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

9. Compounds according to one or more of Claims 1-8, in which B is phenyl, pyridyl, pyridyl N-oxide, thienyl, fury!, pyrrolyl, pyridaz- inyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thia- zolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl, isoquino- linyl, cinnolinyl, phthalazinyl, quinazolinyl or quinoxalinyl, each of which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted by R*, R® and/or R®, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

10. Compounds according to one or more of Claims 1-9, in which

J WO 2004/000839 PCT/EP2003/004434 C 101 B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridaz- inyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thia- zolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl, isoquino- linyl, cinnolinyl, phthalazinyl, quinazoliny! or quinoxalinyl, each of which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted by OH, OA, NO2, NH;, NAA, N N /\ _ / H / — No —N_ J Yoo ow we 0 N 0 N HN N Ho \ or N= H ’ / NSN N ~~ and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

11. Compounds according to one or more of Claims 1-10, : in which B is unsubstituted pyridyl, pyridyl N-oxide, thienyl or pyrazinyl, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

12. Compounds according to one or more of Claims 1-11, R'and R? are each, independently of one another, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, X is N or CH, R® is H or A"R’, . Co oo BN Co i

® WO 2004/000839 PCT/EP2003/004434 C 102 A" and A" are each, independently of one another, absent or alkylene having 1-10 carbon atoms, in which one CH, group may be replaced by NH or NR®, A" and A" together are alternatively an alkylene chain having 2-7 carbon atoms, in which one CH, group may be replaced by NH or NR®, B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazoliny! or quinoxalinyl, each of which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted by OH, OA, NO, NHy, NAA R’ is H, COOH, NHA or NAA, R® is alkyl having 1-6 carbon atoms, A and A are each, independently of one another, alkyl having 1-10 carbon atoms, in which 1-7 H atoms may be replaced by F and/or Cl, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

13. Compounds according to one or more of Claims 1-12, in which R' is 4-methoxy or 4-ethoxy, R? is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or 3-cyclo- pentyloxy, X is N, R’ is H or alkyl having 1-6 carbon atoms, B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl

N . So ME

® WO 2004/000839 PCT/EP2003/004434 ® 103 or quinoxalinyl, each of which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted by OH, OA, NO,, NH;, NAA N N ZN _H / H / Ny N 7 KR NO GI oO N 0 N HN N _X 4 \ or N— } 1 7 NO _N N ~~ R’ is H, R® is alkyl having 1-6 carbon atoms, A and A’ are each, independently of one another, alkyl having 1-10 carbon atoms, in which 1-7 H atoms may be replaced by F and/or Ci, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

14. Compounds according to one or more of Claims 1-13, in which R' is 4-methoxy or 4-ethoxy, R® is 3-methoxy, 3-ethoxy, 3-propoxy, 3-iSopropoxy or 3-cyclopentyloxy, X is N, rR is H or alkyl having 1-6 carbon atoms, \Y is HH, WwW is O, B is unsubstituted pyridyl, pyridyl N-oxide, thienyl or pyrazinyl,

® WO 2004/000839 PCT/EP2003/004434 C 104 and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

15. Compounds according to one or more of Claims 1-14, in which R' is 4-methoxy or 4-ethoxy, R? is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or 3-cyclo- pentyloxy, X is N, R® is H or alkyl having 1-6 carbon atoms, AY is HH, WwW is O, B is unsubstituted pyridyl, pyridyl N-oxide, thienyi or pyrazinyl or phenyl, which is unsubstituted or may be monosubstituted by OH, OA, NO, NH, NAA N N Y N= N= Oo N 0 N HN ~ N el or N— H A NG A and A’ are each, independently of one another, alkyl having 1-10 carbon atoms, in which 1-7 H atoms may be replaced by F and/or Cl, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. . } So In

® WO 2004/000839 PCT/EP2003/004434

16. Compounds of the formula | according to Claim 1 from the group consisting of a) 1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyrid- azin-1-yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yljmethanone, b) 1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1- yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-ylJmethanone, Cc) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]- 1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-ylJmethanone, d) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]- 1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone, e) 1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1- yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone, f) 1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyrid- azin-1-yl}-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone, a) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]- 1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone, h) 1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1- yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone, i) 1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dinydro-4H-pyrid- azin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone, I) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]- 1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone, K) 1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1- yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone, 1) 1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyrid- azin-1-yl}-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yt)methanone, m) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]- 1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone, n) 1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1- yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone,

0) 1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyrid- azin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone, Pp) 1-[3-(3-ethoxy-4-methoxypheny!)-5,6-dihydro-4H-pyridazin-1-yi]- 1-[4-methyl-2-phenylthiazol-5-yllmethanone, qQ) 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dinydro-4H-pyridazin-1-yl]- 1-[4-methyl-2-(4-methoxyphenyl)thiazol-5-ylimethanone, r 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl}- 1-[4-methyl-2-(4-aminophenyl)thiazol-5-ylimethanone, S) 2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyrida- zine-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]malononitrile, t) 2-[(4-{5-[3-(3-ethoxy-4-methoxypheny!)-5,6-dihydro-4H-pyrida- zine-1-carbonyl]-4-methylthiazol-2-y!}phenyl)hydrazono}-2-(1H-tetrazol-5- yl)acetonitrile, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

17. Compounds of the formula | according to one or more of Claims 1 to 16 as phosphodiesterase IV inhibitors.

18. Process for the preparation of compounds of the formula | and salts and solvates thereof, characterised in that a) for the preparation opf a compound of the formula | in which V is

H.Hand Wis O, a compound of the formula I R1 R2 N—N in which R' and R? are as defined in Claim 1, is reacted with a compound of the formula lll

® 107 © JH Hi R3 in which L is Cl, Br, | or a free or reactively functionally modified OH group, and R® X and B are as defined in Claim 1, with the proviso that any further OH and/or amino group present is protected, and subsequently, if desired, a protecting group is removed, and/or b) one or more radicals R', R?, R® and/or B in a compound of the formula | are converted into one or more other radicals R', R?, R® and/or B by 0) cleaving an ether or ester, ii) alkylating or acylating an OH function, iil) reductively alkylating an amino group, iv) reacting an amino group with malononitrile, v) converting a cyano group into a tetrazole group, and/or in that a basic compound of the formula | is converted into one of its salts by treatment with an acid.

19. Medicaments comprising at least one compound of the formula according to one or more of Claims 1 to 16 and/or pharmaceutically usable derivatives, solvates, stereoisomers thereof, including mixtures thereof in all ratios, and, if desired, excipients and/or adjuvants.

® WO 2004/000839 PCT/EP2003/004434 ® 108

20. Use of compounds of the formula | according to one or more of Claims 1 to 16 and/or physiologically acceptable salts or solvates thereof for the preparation of a medicament for the treatment of a patient suffering from a disease or condition mediated by the PDE IV isozyme in its role in regulating the activation and degranulation of human eosino- phils.

21. Use according to Claim 20 of compounds of the formula | accord- ing to one or more of Claims 1 to 16 and/or physiologically acceptable salts or solvates thereof for the preparation of a medicament for combat- ing allergic diseases, asthma, chronic bronchitis, atopic dermatitis, pso- riasis and other skin diseases, inflammatory diseases, autoimmune dis- eases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour meta- stases, sepsis, memory disorders, atherosclerosis and AIDS.

22. Use according to Claim 20 or 21 of a compound of the formula according to Claims 1 to 16 for the preparation of a medicament for the treatment or prevention of one or more of the diseases, pathological dis- orders and conditions from the following group: asthma of whatever type, etiology or pathogenesis, or asthma selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic, IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological dis- turbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome;

® WO 2004/000839 PCT/EP2003/004434 C 109 chronic or acute bronchoconstriction, chronic bronchitis, small air- way obstruction and emphysema; obstructive or inflammatory airway disease of whatever type, etiol- ogy or pathogenesis, or an obstructive or inflammatory airway disease selected from the group consisting of asthma; pneumoconiosis, chronic eosinophilic pneumonia; chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, pulmonary emphysema or dyspnoea associated therewith, COPD that is characterised by irreversible, pro- gressive airway obstruction, acute respiratory distress syndrome (ARDS), and exacerbation of airway hypersensitivity consequent to other medica- ment therapy; pneumoconiosis of whatever type, etiology or pathogenesis, or pneumoconiosis selected from the group consisting of aluminosis, anthra- cosis (asthma), asbestosis, chalicosis, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis, byssinosis or cotton-dust pneumoconiosis and talc pneumoconiosis, bronchitis of whatever type, etiology or pathogenesis, or bronchi- tis selected from the group consisting of acute bronchitis, acute laryngo- tracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis; and vesicular bronchitis; bronchiectasis of whatever type, etiology or pathogenesis, or bronchiectasis selected from the group consisting of cylindric bronchiec- tasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bron- chiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bron- chiectasis; seasonal allergic rhinitis, perennial allergic rhinitis, or sinusitis of whatever type, etiology or pathogenesis, or sinusitis selected from the group consisting of purulent or nonpurulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis;

® WO 2004/000839 PCT/EP2003/004434 ® 110 rheumatoid arthritis of whatever type, etiology or pathogenesis, or rheumatoid arthritis selected from the group consisting of acute arthritis, acute gouty arthritis, primary chronic arthritis, osteoarthrosis, infectious arthritis, Lyme arthritis, progressive arthritis, psoriatic arthritis and spondylarthritis; gout, and fever and pain associated with inflammation; an eosinophil-related pathological disorder of whatever type, etiology or pathogenesis, or an eosinophil-related pathological disorder selected from the group consisting of eosinophilia, pulmonary infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical : pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, eosinophilic granuloma, allergic granulomatous angijtis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotising vasculitis; atopic dermatitis, allergic dermatitis, or allergic or atopic eczema; urticaria of whatever type, etiology or pathogenesis, or urticaria selected from the group consisting of immune-mediated urticaria, com- plement-mediated urticaria, urticariogenic material-induced urticaria, physical stimulus-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angiooedema, cholinergic urti- caria, cold urticaria in the autosomai dominant form or in the acquired form, contact urticaria, giant urticaria and papular urticaria; conjunctivitis of whatever type, etiology or pathogenesis, or con- junctivitis selected from the group consisting of actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, puru- lent conjunctivitis and vernal conjunctivitis; uveitis of whatever type, etiology or pathogenesis, or uveitis selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, chor- oiditis and chorioretinitis; psoriasis;

® 111 multiple sclerosis of whatever type, etiology or pathogenesis, or multiple sclerosis selected from the group consisting of primary progres- sive multiple sclerosis and relapsing remitting multiple sclerosis; autoimmunef/inflammatory diseases of whatever type, etiology or pathogenesis, or an autoimmune/inflammatory disease selected from the group consisting of autoimmune haematological disorders, haemolytic anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombo- cytopenic purpura, systemic lupus erythematosus, polychondritis, sclero- derma, Wegner's granulomatosis, dermatomyositis, chronic active hepati-

tis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases, ulcerative colitis, Crohn's dis- ease, endocrine ophthamopathy, Basedow's disease, sarcoidosis, alveo- litis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juve- nile diabetes or type 1diabetes mellitus, anterior uveitis, granulomatous or posterior uveitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, pul- monary cirrhosis, cystic fibrosis, psoriatic arthritis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory/ hyper-

proliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial pemphigus, pemphigus erythe- matosus, pemphigus foliaceus and pemphigus vulgaris;

prevention of foreign transplant rejection following organ transplantation;

inflammatory bowel disease (IBD) of whatever type, etiology or pathogenesis, or inflammatory bowel disease selected from the group consisting of ulcerative colitis (UC), collagenous colitis, colitis polyposa, transmural colitis and Crohn's disease (CD);

septic shock of whatever type, etiology or pathogenesis, or septic shock selected from the group consisting of renal failure, acute renal fail- ure, cachexia, malarial cachexia, hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia suprarenalis or Addison's disease, cancerous

® WO 2004/000839 PCT/EP2003/004434 ® 112 cachexia, and cachexia as a consequence of infection by the human immunodeficiency virus (HIV); liver damage; pulmonary hypertension and hypoxia-induced pulmonary hyper- tension; bone loss diseases, primary osteoporosis and secondary osteo- porosis; pathological disorders of the central nervous system of whatever type, etiology or pathogenesis, or a pathological disorder of the central nervous system selected from the group consisting of depression, Parkin- son's disease, learning and memory disorders, tardive dyskinesia, drug dependence, arteriosclerotic dementia, and dementias that accompany Huntington's chorea, Wilson's disease, paralysis agitans and thalamic atrophies;

infections, especially viral infections, where these viruses increase the production of TNF-a in their host or where these viruses are sensitive to up-regulation of TNF-a in their host so that their replication or other vital activities are adversely affected, including viruses selected from the group consisting of HIV-1, HIV-2 and HIV-3, cytomegalovirus,

CMV, influenza, adenoviruses and Herpes viruses, including Herpes zoster and Herpes simplex;

yeast and fungal infections, where these yeasts and fungi are sensitive to up-regulation by TNF-a or elicit TNF-a production in their host, for example fungal meningitis, particularly when administered in conjunction with other medicaments of choice for the treatment of sys- temic yeast and fungal infections, including, but not limited to, polymycins, for example polymycin B, imidazoles, for example clotrimazole, econa- zole, miconazole and ketoconazole, triazoles, for example fluconazole and itranazole, and amphotericins, for example amphotericin B and lipo-

somal amphotericin B;

ischaemia-reperfusion damage, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukaemia, HIV infections, lupus \ a

@® WO 2004/000839 PCT/EP2003/004434 ® 113 erythematosus, kidney and ureter diseases, pathological urogenital and gastrointestinal disorders and prostate diseases.

23. Use according to Claim 20, 21 or 22 of a compound of the formula according to Claims 1 to 16 for the preparation of a medicament for the treatment of (1) inflammatory diseases and conditions, including joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel! disease, ulcerative colitis, chronic glomerulonephritis, dermatitis and Crohn's disease; (2) airway diseases and conditions, including asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease and silicosis; (3) infectious diseases and conditions, including sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, fever and myalgia due to bacterial, viral or fungal infections, and influ- enza; (4) immune diseases and conditions, including autoimmune diabe- tes, systemic lupus erythematosus, GvH reaction, rejection of foreign transplants, multiple sclerosis, psoriasis and allergic rhinitis; and (5) other diseases and conditions, including bone absorption diseases, reperfusion damage, cachexia secondary to infection or malignancy, cachexia secon- dary to AIDS, human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC), keloid formation, scar tissue formation, type 1 diabetes mellitus, and leukaemia.

24. Use according to Claim 20 of a compound of the formula | accord- ing to Claims 1 to 16 for the preparation of a medicament for the treat- ment of myocardial diseases.

25. Use according to Claim 24 of a compound of the formula | accord- ing to Claims 1 to 16 for the preparation of a medicament for the treat- ment of myocardial diseases, where these myocardial diseases have inflammatory and immunological properties. \ ”

® WO 2004/000839 PCT/EP2003/004434 ® 114

26. Use according to Claim 20 of a compound of the formula | accord- ing to Claims 1 to 16 for the preparation of a medicament for the treat- ment of coronary heart disease, reversible or irreversible myocardial ischaemiaf/reperfusion damage, acute or chronic heart failure and restenosis, including in-stent restenosis and stent-in-stent restenosis.

27. Combination of a campound according to Claims 1 to 16 together with one or more members of the following group: (a) leukotriene biosynthesis inhibitors: 5-lipoxygenase (5-LO) inhibi- tors and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, N-(5-substituted) thiophene-2-alkylsulfon- amides, 2,6-di-tert-butylphenol hydrazones, Zeneca ZD-2138, SB- 210661, the pyridinyl-substituted 2-cyanonaphthalene compound L-739,010, the 2-cyanoquinoline compound L-746,530, the indole and quinoline compounds MK-591, MK-886 and BAY x 10095; (b) receptor antagonists for the leukotrienes LTB,, LTC4, LTD4 and LTE, selected from the group consisting of the phenothiazin-3-one com- pound L-651,392, the amidino compound CGS-25019c, the benzoxazol- amine compound ontazolast, the benzenecarboximideamide compound BIIL 284/260, the compounds zafirlukast, ablukast, montelukast, praniu- kast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY x 7195; (c) PDE IV inhibitors; (d) 5-lipoxygenase (5-LO) inhibitors; 5-lipoxygenase activating pro- tein (FLAP) antagonists;

® WO 2004/000839 PCT/EP2003/004434 ® 115 (e) dual inhibitors of 5-lipoxygenase (5-L0O) and antagonists of plate- let activating factor (PAF); (f) leukotriene antagonists (LTRAs), including LTB, , LTC, LTD4 and

LTE, antagonists;

(9) antihistamine H; receptor antagonists, including cetirizine, lorata- dine, desloratadine, fexofenadine, astemizole, azelastine and chlorphenir- amine;

(h) gastroprotective H, receptor antagonists;

(i) au- and a,-adrenoreceptor agonist vasoconstrictor sympatho- mimetic agents administered orally or topically for decongestant use,

selected from the group consisting of propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazo- line hydrochloride and ethylnorepinephrine hydrochloride;

f)] one or more a;- and az-adrenoreceptor agonists as listed above under (i) in combination with one or more inhibitors of 5-lipoxygenase (5-LO) as listed above under (a);

(k) anticholinergic agents, including ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine and telenzepine,

(h B1- to Ps-adrenoreceptor agonists selected from the group consist- ing of metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol and pirbuterol;

(m) theophylline and aminophylline;

® WO 2004/000839 PCT/EP2003/004434 ® 116

(n) sodium cromoglycate; (0) muscarinic receptor (M1, M2 and M3) antagonists;

(p) COX-1 inhibitors (NSAIDs) and nitric oxide NSAIDs; (q) the COX-2 selective inhibitor rofecoxib;

(r) insulin-like growth factor type | (IGF-1) mimetics;

(s) ciclesonide, (t) inhalation glucocorticoids with reduced systemic side effects selected from the group consisting of prednisone, prednisolone, fluni-

solide, triamcinolone acetonide, beclomethasone dipropionate, budeson- ide, fluticasone propionate and mometasone furoate; (u) tryptase inhibitors;

(v) platelet activating factor (PAF) antagonists;

- (w) monoclonal antibodies against endogenous inflammatory entities;

(x) IPL 576,

(y) antitumour necrosis factor (TNFa) agents selected from the group consisting of etanercept, infliximab and D2E7, (z) DMARDs selected from the group consisting of leflunomide;

(aa) TCR peptides;

\ Cg

® WO 2004/000839 PCT/EP2003/004434 ® 117 (bb) interleukin converting enzyme (ICE) inhibitors; (ce) IMPDH inhibitors; (dd) adhesion molecule inhibitors, including VLA-4 antagonists;

(ee) cathepsins;

(ff) MAP kinase inhibitors;

(gg) glucose 6-phosphate dehydrogenase inhibitors; (hh) kinin By and B; receptor antagonists;

(il) gold in the form of an aurothio group together with various hydro- philic groups; (i) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine and methotrexate;

(kk) anti-gout agents selected from the group consisting of colchi- cines; (1) xanthine oxidase inhibitors selected from the group consisting of allopurinol; (mm) uricosuric agents selected from the group consisting of probene- cide, sulfinpyrazone and benzbromarone;

(nn) antineoplastic agents, which are antimitotic medicaments selected from the group consisting of vinblastine and vincristine;

Co

® WO 2004/000839 PCT/EP2003/004434 (00) agents for promoting growth hormone secretion; (PP) inhibitors of matrix metalloproteases (MMPs) selected from the group consisting of stromelysins, collagenases, gelatinases, aggreca- nase, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stro- melysin-3 (MMP-11); (qq) transforming growth factor (TGF pf); (rr) platelet-derived growth factor (PDGF); (ss) fibroblast growth factor selected from the group consisting of basic fibroblast growth factor (bFGF), (tt) granulocyte macrophage colony stimulating factor (GM-CSF); (uu) capsaicin; (vv) tachykinin NK; and NK; receptor antagonists selected from the group consisting of NKP-608C; SB233412 (talnetant) and D-4418,; (ww) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and (xx) adenosine A2a receptor agonists.

28. Medicaments comprising at least one compound of the formula according to one or more of Claims 1 to 16 and/or pharmaceutically

& PCT/EP2003/004434 (ww) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and (xx) adenosine A2a receptor agonists.

28. Medicament comprising at least one compound of the formula according to one or more of Claims 1 to 16 and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

29. Set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula | according to one or more of Claims 1 to 16 and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

30. Use of a compound of the formula | according to one or more of Claims 1 to 16 in the manufacture of a preparation for use as phosphodiesterase |V inhibitors.

31. A substance or composition for use in a method of treatment or prevention as phosphodiesterase |V inhibitors, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 16, and said method comprising administering said substance or composition. AMENDED SHEET

/ PCT/EP2003/004434

32. A substance or composition for use in a method for the treatment of a patient suffering from a disease or complaint caused by the PDE IV isozyme in its role in regulating the activation and degranulation of human eosinophils, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 16 and/or physiologically acceptable salts or solvates thereof, and said method comprising administering said substance or composition.

33. A substance or composition for use in a method for combatting allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn’s disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastasis, sepsis, memory disorders, atherosclerosis and AIDS, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 16 and/or physiologically acceptable salts or solvates thereof, and said method comprising administering said substance or composition.

34. A substance or composition for use in a method for the treatment or prevention of one or more diseases, pathological disorders and conditions selected from the group as listed in claim 22, said substance or composition comprising a compound of the formula | according to Claims 1 to 16, and said method comprising administering said substance or composition.

35. A substance or composition for use in a method for the treatment of (1) inflammatory diseases and conditions, including joint inflammation, AMENDED SHEET

¢ PCT/EP2003/004434 rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis and Crohn's disease; (2) respiratory diseases and conditions, including asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease and silicosis; (3) infectious diseases and conditions, including sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions, including autoimmune diabetes, systemic lupus erythematosis, GvH reaction, rejection of foreign transplants, multiple sclerosis, psoriasis and allergic rhinitis; and (5) other diseases and conditions, including bone absorption diseases; reperfusion damage; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus;and leukaemia, said substance or composition comprising a compound of the formula | according to Claims 1 to 16, and said method comprising administering said substance or composition.

36. A substance or composition for use in a method for the treatment of myocardial disease, said substance or composition comprising a compound of the formula | according to Claims 1 to 16, and said method comprising administering said substance or composition.

37. A substance or composition for use in a method for the treatment of myocardial diseases, where these myocardial diseases have inflammatory and immunological properties, said substance or composition comprising a compound of the formula | according to Claims AMENDED SHEET

PCT/EP2003/004434 1 to 16, and said method comprising administering said substance or composition.

38. A substance or composition for use in a method for the treatment of coronary heart disease, reversible or irreversible myocardial ischaemia/reperfusion damage, acute or chronic heart failure and restenosis, including in-stent restenosis and stent-in-stent restenosis, said substance or composition comprising a compound of the formula according to Claims 1 to 16, and said method comprising administering said substance or composition.

39. A compound according to claim 1 , substantially as herein described and illustrated.

40. A substance or composition for use in a method of treatment or prevention according to any one of claims 17, or 31 to 38, substantially as herein described and illustrated.

41. A process according to claim 18, substantially as herein described and illustrated.

42. Medicament according to claim 19, or claim 28, substantially as herein described and illustrated.

43. Use according to any one of claims 20 to 26, or 30, substantially as herein described and illustrated.

44. Combination according to claim 27, substantially as herein described and illustrated. AMENDED SHEET

PCT/EP2003/004434

45. Set (kit) according to claim 29, substantially as herein described and illustrated.

46. A new compound, a substance or composition for a new use in a method of treatment or prevention, a new process for preparing a compound, a new medicament, a new use of a compound according to any one of claims 1 to 16 and/or a physiologically acceptable salt or solvate thereof, a new combination, or a new set (kit), substantially as herein described. AMENDED SHEET